Rosenbloom Joel, Macarak Edward, Piera-Velazquez Sonsoles, Jimenez Sergio A
The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Methods Mol Biol. 2017;1627:1-23. doi: 10.1007/978-1-4939-7113-8_1.
Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue. Critical signaling cascades, initiated primarily by transforming growth factor-β (TGF-β), but also involving numerous cytokines and signaling molecules which stimulate profibrotic reactions in myofibroblasts, offer potential therapeutic targets. Here, we briefly review the current knowledge of the molecular mechanisms involved in the development of tissue fibrosis and point out some of the most important challenges to research in the fibrotic diseases and to the development of effective therapeutic approaches for this often fatal group of disorders. Efforts to further clarify the complex pathogenetic mechanisms of the fibrotic process should be encouraged to attain the elusive goal of developing effective therapies for these serious, untreatable, and often fatal disorders.
人类纤维化疾病是全球范围内的一个主要健康问题，原因在于患病人数众多、对纤维化过程发病机制的了解不全面、病因和临床表现存在显著异质性、缺乏合适且经过充分验证的生物标志物，以及最重要的是，目前缺乏有效的疾病改善治疗药物。纤维化疾病涵盖了广泛的临床实体，包括系统性纤维化疾病，如系统性硬化症（SSc）、硬皮病样移植物抗宿主病和肾源性系统性纤维化，以及许多器官特异性疾病，包括放射性纤维化和心脏、肺、肝和肾纤维化。尽管它们的致病机制多种多样，在某些情况下仍难以捉摸，但这些疾病都有一个共同特征，即受影响器官中纤维化组织不受控制地进行性积累，导致其功能障碍并最终衰竭。尽管纤维化疾病发展的病因机制及其临床表现存在显著异质性，但众多研究已确定活化的肌成纤维细胞是最终导致正常组织被无功能纤维化组织替代的共同细胞成分。主要由转化生长因子-β（TGF-β）启动，但也涉及许多刺激肌成纤维细胞中促纤维化反应的细胞因子和信号分子的关键信号级联反应，提供了潜在的治疗靶点。在此，我们简要回顾目前对组织纤维化发展所涉及分子机制的认识，并指出纤维化疾病研究以及开发针对这一常致命性疾病组的有效治疗方法所面临的一些最重要挑战。应鼓励进一步阐明纤维化过程复杂致病机制的努力，以实现为这些严重、无法治疗且往往致命的疾病开发有效疗法这一难以实现的目标。
